Abstract:

The present invention is directed to processes for the synthesis of
morphinans. In particular, a process for the asymmetric reduction of an
imine moiety in a 3,4-dihydroisoquinoline to produce a
tetrahydroisoquinoline, followed by a Birch reduction to produce a
hexahydroisoquinoline. In various embodiments, the
3,4-dihydroisoquinoline contains a phenol moiety protected with a labile
protecting group. In other embodiments, the imine reduction reaction
mixture contains silver tetrafluoroborate.

Claims:

1. A process for the preparation of a hexahydroisoquinoline corresponding
to Formula 800, the process comprising reducing a tetrahydroisoquinoline
corresponding to Formula 704: ##STR00021## whereinR1 and R7 are
independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or
--OR111;R2 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
halo, or --OR211;R3 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, or --OR311;R4 is hydrogen, hydrocarbyl,
substituted hydrocarbyl, halo, or --OR411;R5 and R6 are
independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or
--OR511;R12 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
halo, or --OR121; R13 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, halo, or --OR511;R17 is hydrogen, or acyl;R21
is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or
--OR215;R31 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
or --OR316;R41 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, halo, or --OR415;R111 is hydrogen, hydrocarbyl, or
substituted hydrocarbyl;R211 is hydrogen, hydrocarbyl,
--C(O)R212, --C(O)NHR213, or --SO2R214;R212,
R213 and R214 are independently hydrocarbyl or substituted
hydrocarbyl;R215 is hydrogen, hydrocarbyl or substituted
hydrocarbyl;R311 is hydrogen, hydrocarbyl, --C(O)R312,
--C(O)NHR313, or --SO2R314;R312, R313, or
R314 are independently hydrocarbyl or substituted
hydrocarbyl;R315 is hydrogen, hydrocarbyl or substituted
hydrocarbyl;R411 is hydrogen, hydrocarbyl, --C(O)R412,
--C(O)NHR413, or --SO2R414;R412 is hydrogen, alkyl or
aryl, provided, R412 is other than phenyl;R413, and R414
are independently hydrocarbyl or substituted hydrocarbyl;R415 is
hydrogen, hydrocarbyl or substituted hydrocarbyl;R511 is hydrogen,
hydrocarbyl, or substituted hydrocarbyl; andR121 is hydrogen,
hydrocarbyl, or substituted hydrocarbyl;wherein either R1 is
hydroxyl, and/or at least one of R2, R3, or R4 is
hydroxyl, --OC(O)R212, --OC(O)NHR213, --OSO2R214,
--OC(O)R312, --OC(O)NHR313, --OSO2R314,
--OC(O)R412, --OC(O)NHR13, or --OSO2R.sub.414.

2. The process of claim 1, wherein:R2 is --OR211;R211 is
hydrogen, alkyl, --C(O)R212, --C(O)NHR213, or
--SO2R214; andR212, R213, and R214 are
independently alkyl or aryl.

3. The process of claim 1, wherein:R3 is --OR311;R311 is
hydrogen, alkyl, --C(O)R312, --C(O)NHR313, or
--SO2R314; andR312, R313, and R314 are
independently alkyl or aryl.

4. The process of claim 1, wherein:R4 is --OR411;R411 is
hydrogen, alkyl, --C(O)R412, --C(O)NHR413, or
--SO2R414;R412 is alkyl or aryl, provided, R412 is
other than phenyl; andR413 and R414 are independently alkyl or
aryl.

7. The process of claim 1, wherein:R2 is --OR211;R211 is
hydrogen, alkyl, --C(O)R212, --C(O)NHR213, or
--SO2R214; andR212, R213, and R214 are
independently alkyl or aryl:R3 is --OR311;R311 is
hydrogen, alkyl, --C(O)R312, --C(O)NHR313, or
--SO2R314; andR312, R313, and R314 are
independently alkyl or aryl;R4 is --OR411;R411 is
hydrogen, alkyl, --C(O)R412, --C(O)NHR413, or
--SO2R414;R412 is alkyl or aryl, provided, R412 is
other than phenyl; andR413 and R414 are independently alkyl or
aryl.

11. The process of claim 1, wherein R3 is methoxy, R4 is
hydroxyl, --OC(O)CH3, --OC(O)Ph, or --OSO2CH3, R6 is
methoxy, and R1, R2, R5, R7, R12, and R13
are hydrogen.

12. The process of claim 1, wherein a reducing agent reduces the
tetrahydroisoquinoline to the hexahydroisoquinoline, the reducing agent
comprising an alkali metal and/or an electron source.

13. The process of claim 12, wherein the alkali metal is chosen from
lithium, sodium and potassium and the electron source is chosen from
liquid ammonia, methylamine, ethylamine, ethylenediamine, and
combinations thereof.

22. The compound of claim 15, wherein:R2 is --OR211;R211 is
hydrogen, alkyl, --C(O)R212, --C(O)NHR213, or
--SO2R214; andR212, R213, and R214 are
independently alkyl or aryl;R3 is --OR311;R311 is
hydrogen, alkyl, --C(O)R312, --C(O)NHR313, or
--SO2R314; andR312, R313, and R314 are
independently alkyl or aryl;R4 is --OR411;R411 is
hydrogen, alkyl, --C(O)R412--C(O)NHR413, or
--SO2R414; andR413, and R414 are independently alkyl
or aryl.

Description:

[0001]This application is a divisional of U.S. patent application Ser. No.
12/518,430 filed on Jun. 10, 2009 and entitled "PREPARATION OF
TETRAHYDROISOQUINOLINES FROM DlHYDROISOQUINOLINES", which claims priority
to PCT application of PCT/US2007/025262, filed Dec. 10, 2007 and entitled
"PREPARATION OF HEXAHYDROISOQUINOLINES FROM DIHYDROISOQUINOLINES", which
claims the benefit of U.S. Provisional Application No. 60/874,456 filed
Dec. 12, 2006--

FIELD OF THE INVENTION

[0002]The present invention generally relates to processes for the
synthesis of intermediates used to prepare morphinans. More specifically,
the invention is directed to the synthesis of hexahydroisoquinolines and
their analogs from dihydroisoquinolines.

BACKGROUND OF THE INVENTION

[0003]Hexahydroisoquinoline and its derivatives are important synthetic
intermediates to many morphinan compounds including burprenorphine,
codeine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphine,
nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally,
these compounds are analgesics, which are used extensively for pain
relief in the field of medicine due to their action as opiate receptor
agonists. However, nalmefene, naloxone and naltrexone are opiate receptor
antagonists; they are used for reversal of narcotic/respiratory
depression due to opiate receptor agonists.

[0004]Rice (U.S. Pat. No. 4,521,601) discloses the reduction of a
dihydroisoquinoline to a tetrahydroisoquinoline by contacting the
dihydroisoquinoline with sodium cyanoborohydride or sodium borohydride in
refluxing 45% methanol for 1.5 hours. Rice further discloses Birch
reduction of a tetrahydroisoquinoline to a hexahydroisoquinoline with
lithium or sodium in liquid ammonia at -55° C. to -65° C.
for 4 hours, then at -75° C. until none of the starting
tetrahydroisoquinoline remains by thin layer chromatography. Because the
borohydride reduction of a dihydroisoquinoline occurs in an achiral
environment, the resulting tetrahydroisoquinoline must be resolved before
further reaction. This resolution adds an extra step and reduces the
yield of the desired enantiomer as half of the product has the undesired
stereochemistry.

[0005]Uematsu et al. (J. Am. Chem. Soc. 1996, 113, 4916-4917) and
Meuzelaar, et al. (Eur. J. Org. Chem. 1999, 2315-2321) disclose the
asymmetric reduction of a dihydroisoquinoline with a chiral ruthenium
catalyst in the presence of a 5:2 formic acid-triethylamine azeotropic
mixture of salts in various aprotic solvents These transformations
typically have a reaction time of about 3 hours. Thus, more efficient
processes having higher yields and enantiomeric excesses are desirable.

SUMMARY OF THE INVENTION

[0006]Among the various aspects of the invention is a process for the
preparation of a 1,2,3,4-tetrahydroisoquinoline corresponding to Formula
700 comprising treating a 3,4-dihydroisoquinoline corresponding to
Formula 600 with an asymmetric catalyst in the presence of silver
tetrafluoroborate, and a hydrogen source. The chemical structures
corresponding to Formulae 600 and 700 are

[0007]Another aspect is a process for the preparation of a
tetrahydroisoquinoline corresponding to Formula 701 comprising treating a
3,4-dihydroisoquinoline corresponding to Formula 601 with an asymmetric
catalyst in the presence of a hydrogen source. The chemical structures
corresponding to Formulae 601 and 701 are

[0010]Other objects and features will be in part apparent and in part
pointed out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

[0011]The present invention is directed to an improved synthetic method
for preparing optically active hexahydroisoquinolines. Among the various
aspects of the present invention is the preparation of various
hexahydroisoquinolines (Formula 800) from the stepwise reduction of
particular dihydroisoquinolines (Formulae 600 and 601). For example, in
some of the various embodiments, a dihydroisoquinoline is reduced in the
presence of a hydrogen source, an asymmetric catalyst, and, optionally,
silver tetrafluoroborate to produce an optically active
tetrahydroisoquinoline (Formulae 700, 701, and 702). The optically active
tetrahydroisoquinoline can subsequently undergo a Birch reduction by
contact with a reducing agent to form a hexahydroisoquinoline (Formula
800) without loss of optical activity. Various dihydroisoquinolines
(Formula 601) and tetrahydroisoquinolines (Formulae 701 and 702) of the
invention are substituted with ester, amide, or sulfonate ester
protecting groups in order to facilitate reaction and isolation of
intermediates.

[0012]Generally, the processes for the synthetic transformations of the
invention described above are depicted in Reaction Scheme 1 below.

##STR00005##

Each of these compounds and synthetic steps are described in more detail
below.

Hexahydrolsoquinolines

[0013]As described above for Reaction Scheme 1, an aspect of the present
invention is a process for preparing hexahydroisoquinolines corresponding
to Formula 800

[0028]Although R21 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
halo, or --OR215, in some of the various embodiments, R21 is
hydrogen or --OR215. In some of these embodiments, R215 is
hydrogen, alkyl, or aryl. Preferably, R215 is hydrogen or alkyl.
More preferably, R215 is hydrogen, methyl, ethyl, propyl, butyl,
pentyl, hexyl, or phenyl. In some of the various embodiments, R215
is hydrogen, methyl, or phenyl.

[0029]Similarly, although R31 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, or --OR315, in some embodiments, R31 is hydrogen
or --OR315. In some of these embodiments, R316 is hydrogen,
alkyl, or aryl. Preferably, R315 is hydrogen or alkyl. More
preferably, R315 is hydrogen, methyl, ethyl, propyl, butyl, pentyl,
hexyl, or phenyl. In some of the various embodiments, R315 is
hydrogen, methyl, or phenyl.

[0030]As noted above, R41 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, halo, or --OR415, in some embodiments, R41 is
hydrogen or --OR415. In some of these embodiments, R415 is
hydrogen, alkyl or aryl. More preferably, R415 is hydrogen, methyl,
ethyl, propyl, butyl, pentyl, hexyl, or phenyl. In some of the various
embodiments, R415 is hydrogen, methyl, or phenyl.

[0031]Further, R6 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
or --OR511, in some embodiments, R6 is hydrogen or
--OR511. In some of these embodiments, R511 is hydrogen, alkyl,
or aryl. Preferably, R511 is hydrogen, methyl, ethyl, propyl, butyl,
pentyl, hexyl, or phenyl; more preferably, methyl.

[0033]In many of the various embodiments, R1, R5, R7, and
R13 are hydrogen.

[0034]In combination, among the preferred embodiments are
hexahydroisoquinolines corresponding to Formula 800 wherein R21 is
hydrogen or --OR215 wherein R215 is hydrogen, alkyl, or aryl.
In some embodiments, R215 is hydrogen or methyl. In these
embodiments, R31 is hydrogen or --OR315. In various preferred
embodiments, R315 is hydrogen, alkyl, or aryl, preferably, R315
is hydrogen or alkyl. In some of these embodiments, R315 is hydrogen
or methyl. Further, R41 is hydrogen or --OR415. In various
embodiments, R415 is hydrogen, alkyl, or aryl, preferably, R415
is hydrogen or alkyl. In some embodiments, R415 is hydrogen or
methyl. Further yet, R6 is hydrogen or --OR511. In some of
these embodiments, R511 is hydrogen, methyl, ethyl, propyl, butyl,
pentyl, hexyl, or phenyl; preferably, hydrogen or methyl. Additionally,
R12 is hydrogen, alkyl, allyl, benzyl, or halo. In many of these
embodiments, R1, R5, R7, and R13 are hydrogen.

Tetrahydrolsoquinolines

[0035]As described in Reaction Scheme 1, a tetrahydroisoquinoline
corresponding to Formula 700 has the structure

[0058]Although R2 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
halo, or --OR211, in some of the various embodiments, R2 is
hydrogen or --OR211. In some of these embodiments, R211 is
hydrogen, alkyl, aryl, --C(O)R212, --C(O)NHR213, or
--SO2R214. Preferably, R211 is hydrogen, alkyl, or
--C(O)R212 wherein R212 is alkyl or aryl. More preferably,
R211 is --C(O)R212 wherein R212 is methyl, ethyl, propyl,
butyl, pentyl, hexyl, or phenyl. In some of the various embodiments,
R211 is --C(O)R212 wherein R212 is ethyl, propyl, butyl,
pentyl, or hexyl.

[0059]Similarly, although R3 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, or --OR311, in some embodiments, R3 is hydrogen or
--OR311. In some of these embodiments, R311 is hydrogen, alkyl,
aryl, --C(O)R312, --C(O)NHR313, or --SO2R314.
Preferably, R311 is hydrogen, alkyl, or --C(O)R312 wherein
R312 is alkyl or aryl. More preferably, R311 is --C(O)R312
wherein R312 is methyl, ethyl, propyl, butyl, pentyl, hexyl, or
phenyl. In some of the various embodiments, R311 is --C(O)R312
wherein R312 is ethyl, propyl, butyl, pentyl, or hexyl.

[0060]As noted above, R4 is hydrogen, hydrocarbyl, substituted
hydrocarbyl, halo, or --OR411, in some embodiments, R4 is
hydrogen or --OR411. In some of these embodiments, R411 is
hydrogen, alkyl, aryl, --C(O)R412, --C(O)NHR413, or
--SO2R414. Preferably, R411 is hydrogen, alkyl, or
--C(O)R412 wherein R412 is alkyl or aryl. More preferably,
R411 is --C(O)R412 wherein R412 is ethyl, propyl, butyl,
pentyl, or hexyl.

[0061]Further, R6 is hydrogen, hydrocarbyl, substituted hydrocarbyl,
or --OR511, in some embodiments, R6 is hydrogen or
--OR511. In some of these embodiments, R511 is hydrogen, alkyl,
or aryl. Preferably, R511 is hydrogen, methyl, ethyl, propyl, butyl,
pentyl, hexyl, or phenyl; more preferably, methyl.

[0063]In many of the various embodiments, R1, R5, R7, and
R13 are hydrogen.

[0064]In combination, among the preferred embodiments are
tetrahydroisoquinolines corresponding to Formulae 700, 701, 702, and 703
wherein R2 is hydrogen or --OR211 wherein R211 is
hydrogen, alkyl, or --C(O)R212 wherein R212 is alkyl or aryl.
In some embodiments, R212 is ethyl, propyl, butyl, pentyl, or hexyl.
In these embodiments, R311 is hydrogen or --OR311. In various
preferred embodiments, R311 is hydrogen, alkyl, aryl, or
--C(O)R312, preferably, R311 is hydrogen, alkyl, or
--C(O)R312 wherein R312 is alkyl or aryl. In some of these
embodiments, R312 is ethyl, propyl, butyl, pentyl, or hexyl.
Further, R4 is hydrogen or --OR411. In various embodiments,
R411 is hydrogen, alkyl, aryl, or --C(O)R412, preferably,
R411 is hydrogen, alkyl, or --C(O)R412 wherein R412 is
alkyl or aryl. In some embodiments, R412 is methyl, ethyl, propyl,
butyl, pentyl, hexyl, or phenyl. Alternatively, R412 is ethyl,
propyl, butyl, pentyl, or hexyl. Further yet, R6 is hydrogen or
--OR511. In some of these embodiments, R511 is hydrogen,
methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl; preferably,
methyl. Additionally, R12 is hydrogen, alkyl, allyl, benzyl, or
halo. In many of these embodiments, R1, R5, R7, and
R13 are hydrogen.

Dihydroisoquinolines

[0065]As described above for Reaction Scheme 1, a 3,4-dihydroisoquinoline
corresponding to Formula 600 has the structure

[0068]Generally, compounds of Formulae 600 and 601 can be prepared by
methods described by Rice in U.S. Pat. No. 4,521,601, herein incorporated
by reference. Further, these compounds can be prepared by methods
described by Kashdan et al. (J. Org. Chem. 1982, 47 2638-2643) and by
Beyerman et al. (J. Royal Netherlands Chem. Soc. 1978, 97(5), 127-130),
and by copending application U.S. Application Ser. No. 60/874,131
(Attorney Docket No. H-MP-00021), herein incorporated by reference.

Asymmetric Reduction of a 3,4-Dihydroisoquinoline to a
Tetrahydroisoquinoline

[0069]For the process of the present invention, the structures of the
products (e.g., hexahydroisoquinolines), reactants (e.g.,
3,4-dihydroisoquinolines) and intermediates (e.g.,
tetrahydroisoquinolines) are described above. The first step of this
process comprises a reduction of the imine moiety in a
3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline. This imine
reduction reaction mixture typically contains the
3,4-dihydroisoquinoline, the asymmetric catalyst, and a hydrogen source.
The imine reduction reaction mixture can optionally contain silver
tetrafluoroborate.

[0070]This imine reduction reaction forms another chiral center in the
tetrahydroisoquinoline, and thus, preferably, occurs in an asymmetric
environment. In various embodiments, the process of the invention uses an
asymmetric catalyst to provide an asymmetric environment for the
reduction of the imine moiety. The asymmetric catalyst comprises a metal
or metal source and a chiral ligand. The metal or metal source is
selected from ruthenium, a ruthenium complex, osmium, an osmium complex,
rhodium, a rhodium complex, iridium, iridium complex, and combinations
thereof. The chiral ligand can have the structure of formulae 670 or 680

##STR00009##

wherein R671, R672, and R673 are independently alkyl or
aryl and wherein R681 is alkyl or aryl.

[0071]In various preferred embodiments, the chiral ligand can have the
structure of 670 wherein R672 and R673 are phenyl and R671
is aryl. In some of these embodiments, R671 can be tolyl, mesityl,
or naphthyl. In various preferred embodiments, the chiral ligand can be
(1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine or
(1R,2R)-(-)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine,
depending on which enantiomer is the desired product. In other
embodiments, the chiral ligand can have the structure of 680 wherein
R681 is tolyl, mesityl, 2,4,6-triisopropylphenyl, or naphthyl. In
particular embodiments, R6$1 can be p-tolyl,
2,4,6-triisopropylphenyl, 1-naphthyl, or 2-naphthyl.

[0072]In various preferred embodiments, the asymmetric catalyst comprises
a ruthenium source comprising dichloro(p-cymene) ruthenium (11) dimer and
a chiral ligand comprising
(1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine.
Typically, about 0.005 g to about 0.015 g of asymmetric catalyst per gram
of starting 3,4-dihydroisoquinoline is present in the imine reduction
reaction mixture.

[0073]The rate of the imine reduction reaction is directly proportional to
the concentration of asymmetric catalyst (e.g., metal or metal source and
chiral ligand) used. For example, an imine reduction reaction mixture
that contains a greater amount of asymmetric catalyst has a shorter
reaction time than a reaction mixture that contains a smaller amount of
asymmetric catalyst.

[0074]In some of the embodiments, the hydrogen source for the imine
reduction comprises protic compounds (including alcohol and formic acid).
Preferably, the hydrogen source is a protic compound comprising a
carboxylic acid. Particularly, the hydrogen source comprises a formic
acid-triethylamine azeotropic mixture of salts; preferably, this mixture
has a ratio of formic acid to triethyl amine of about 5:2. About 3
equivalents to about 3.5 equivalents of triethylamine and about 7.5
equivalents to about 8 equivalents of formic acid are used for each
equivalent of 3,4-dihydroisoquinoline.

[0075]In various preferred embodiments, the reaction mixture can contain
silver tetrafluoroborate. Typically, the silver tetrafluoroborate is
present in similar amounts as the asymmetric catalyst and typically,
ranges from about 0.005 g to about 0.015 g of silver tetrafluoroborate
per gram of starting 3,4-dihydroisoquinoline present in the imine
reduction reaction mixture. The addition of silver tetrafluoroborate
increases the reaction rate. For example, the reaction time for the
reduction in the presence of silver tetrafluoroborate is about 30% to
about 50% shorter than the reaction time for the reduction in the absence
of silver tetrafluoroborate.

[0076]Upon addition of the formic acid and triethylamine to the reaction
mixture, there is an exotherm; this exotherm is followed by cooling of
the reaction mixture and addition of the 3,4-dihydroisoquinoline and the
asymmetric catalyst. The imine reduction occurs at a temperature of from
about 10° C. to about 40° C.; preferably, from about
20° C. to about 30° C.; more preferably, from about
24° C. to about 26° C. The imine reduction reaction mixture
is allowed to react for about 4 hours to about 24 hours; preferably for
about 18 hours.

[0078]Upon completion of the imine reduction, the product
tetrahydroisoquinoline precipitates from the solution and can be isolated
by methods known in the art. For example, the product can be collected by
filtration of the reaction mixture followed by washing the product solid
with the solvent.

Birch Reduction of a Tetrahydroisoquinoline to a Hexahydroisoquinoline

[0079]The second step of the process of the invention is a Birch reduction
of a tetrahydroisoquinoline (Formulae 700, 701, 702, and 703) to form a
hexahydroisoquinoline (Formula 800). The Birch reduction is generally
effected using a reducing agent. Thus, the Birch reduction reaction
mixture comprises a tetrahydroisoquinoline and a reducing agent.
Exemplary reducing agents comprise an alkali metal and at least one of
liquid ammonia, methylamine, ethylamine, ethylenediamine, and
combinations thereof. Preferably, the reducing agent for the Birch
reduction comprises lithium metal and liquid ammonia. In alternative
embodiments, the reducing agent comprises lithium metal, sodium metal,
potassium metal, or calcium metal and methylamine or ethylamine.

[0080]The Birch reduction reaction mixture typically also includes a
solvent mixture. This solvent mixture comprises isopropyl alcohol (IPA),
t-butyl alcohol, tetrahydrofuran (THF), ammonia, and combinations
thereof. Preferably, the solvent comprises IPA, THF, and ammonia; and, in
some embodiments, the ratio of IPA to THF to liquid ammonia is 1 to 2 to
3. Depending on the reagents used, the Birch reduction occurs at a
temperature of from about -80° C. to about 10° C. When
liquid ammonia is used as a reagent, the reduction takes place at about
-80° C. to about -35° C. When methylamine or ethylamine is
used as a reagent, the reduction takes place at a temperature from about
-10° C. to about 10° C. The Birch reduction reaction
mixture is maintained at the above temperatures for about 10 minutes to
about 4 hours.

[0081]Typically, the tetrahydroisoquinoline was suspended or dissolved in
a cosolvent such as tetrahydrofuran ort-butyl alcohol. This mixture was
cooled to -10° C. and methylamine was added and the temperature
was maintained at -10° C. The lithium metal was charged in
portions and the reaction mixture was stirred at -10° C. for
another 30 minutes to about 2 hours after sufficient lithium metal was
charged. The reaction mixture was warmed to room temperature and then
added to water to produce the product hexahydroisoquinoline as a
precipitate.

Uses of Intermediates

[0082]The above-described synthesis stages are important in the
preparation of morphinans and analogs thereof. General reaction schemes
for the preparation of morphinans are disclosed in U.S. Pat. No.
4,368,326 to Rice, the entire disclosure of which is incorporated by
reference. The morphinans and analogs thereof (i.e., the morphinans
contain an X group of N--(R17) or N+-(R17aR17b)) of
interest in the practice of the present invention are opiate receptor
agonists or antagonists and generally are compounds corresponding to
Formula (24)

[0090]R62 and R63 are independently hydrogen, alkyl, alkenyl,
alkynyl, allyl, alkoxy, alkylthio, acyloxy, or aryl, together form keto,
or together with the carbon atom to which they are attached form a ketal,
dithioketal, or monoketal;

[0091]R71 and R81 are independently hydrogen, hydrocarbyl,
substituted hydrocarbyl, or halo; and

[0093]In a particular embodiment, the products and intermediates produced
according to the present invention are useful in the preparation of a
morphinan compound corresponding to Formula (24) wherein X is
--N(R17)-- and R17 is defined as above.

[0094]For purposes of clarity, the carbon atoms of Formulae (S), (T), (U),
(V), (W), (X), (Y), and (Z) corresponding to A6, A7, A8,
and A14 of Formula (24), respectively, have been identified (by
indicating with an arrow which carbon atom corresponds to each). Further,
squiggly lines have been included in Formulae (S), (T), (U), (V), (W),
(X), (Y), and (Z) to indicate the points of attachment to the polycyclic
ring of Formula (24).

[0095]Exemplary morphinans that may be produced according to a variety of
methods include, for instance, nordihydrocodeinone (i.e., Formula (24)
wherein R11, R17, and R22 are hydrogen, R33 is
methoxy, X is --N(R17)--, and -A6-A7-A8-A14-
corresponds to Formula (Y) wherein R14 is hydrogen, R62 and
R63 together form keto, and R71 and R81 are hydrogen)
(which corresponds to Formula (241) below); dihydrocodeinone (i.e.,
Formula (24) wherein R11, and R22 are hydrogen, R17 is
methyl, R33 is methoxy, X is --N(R17)--, and
-A6-A7-A8-A14- corresponds to Formula (Y) wherein
R14 is hydrogen, R62 and R63 together form keto, and
R71 and R81 are hydrogen) (which corresponds to Formula (242)
below); noroxymorphone (i.e., Formula (24) wherein R11, R17,
and R22 are hydrogen, R33 is hydroxy, X is --N(R17)--, and
-A6-A7-A8-A14- corresponds to Formula (Y) wherein
R14 is hydroxy, R62 and R63 together form keto, and
R71 and R81 are hydrogen) (which corresponds to Formula (243)
below); and salts, intermediates, and analogs thereof.

##STR00013##

DEFINITIONS

[0096]The term "acyl," as used herein alone or as part of another group,
denotes the moiety formed by removal of the hydroxyl group from the group
COOH of an organic carboxylic acid, e.g., RC(O)--, wherein R is R1,
R1O--, R1R2N--, or R1S--, R1 is hydrocarbyl,
heterosubstituted hydrocarbyl, substituted hydrocarbyl, or heterocyclo,
and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.

[0097]The term "acyloxy," as used herein alone or as part of another
group, denotes an acyl group as described above bonded through an oxygen
linkage (O), e.g., RC(O)O-- wherein R is as defined in connection with
the term "acyl."

[0098]The term "alkyl" as used herein describes groups which are
preferably lower alkyl containing from one to eight carbon atoms in the
principal chain and up to 20 carbon atoms. They may be straight or
branched chain or cyclic and include methyl, ethyl, propyl, isopropyl,
butyl, hexyl and the like.

[0099]The term "alkenyl" as used herein describes groups which are
preferably lower alkenyl containing from two to eight carbon atoms in the
principal chain and up to 20 carbon atoms. They may be straight or
branched chain or cyclic and include ethenyl, propenyl, isopropenyl,
butenyl, isobutenyl, hexenyl, and the like.

[0100]The term "alkynyl" as used herein describes groups which are
preferably lower alkynyl containing from two to eight carbon atoms in the
principal chain and up to 20 carbon atoms. They may be straight or
branched chain and include ethynyl, propynyl, butynyl, isobutynyl,
hexynyl, and the like.

[0101]The term "aromatic" as used herein alone or as part of another group
denotes optionally substituted homo- or heterocyclic aromatic groups.
These aromatic groups are preferably monocyclic, bicyclic, or tricyclic
groups containing from 6 to 14 atoms in the ring portion. The term
"aromatic" encompasses the "aryl" and "heteroaryl" groups defined below.

[0102]The term "aryl" as used herein alone or as part of another group
denote optionally substituted homocyclic aromatic groups, preferably
monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring
portion, such as phenyl, biphenyl, naphthyl, substituted phenyl,
substituted biphenyl or substituted naphthyl. Phenyl and substituted
phenyl are the more preferred aryl.

[0103]The terms "halogen" or "halo" as used herein alone or as part of
another group refer to chlorine, bromine, fluorine, and iodine.

[0104]The term "heteroatom" shall mean atoms other than carbon and
hydrogen.

[0105]The terms "heterocyclo" or "heterocyclic" as used herein alone or as
part of another group denote optionally substituted, fully saturated or
unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups
having at least one heteroatom in at least one ring, and preferably 5 or
6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen
atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the
remainder of the molecule through a carbon or heteroatom. Exemplary
heterocyclo groups include heteroaromatics as described below. Exemplary
substituents include one or more of the following groups: hydrocarbyl,
substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy,
alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano,
ketals, acetals, esters and ethers.

[0106]The term "heteroaryl" as used herein alone or as part of another
group denote optionally substituted aromatic groups having at least one
heteroatom in at least one ring, and preferably 5 or 6 atoms in each
ring. The heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1 to
4 nitrogen atoms in the ring, and is bonded to the remainder of the
molecule through a carbon. Exemplary heteroaryls include furyl,
benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl,
benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl,
indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl,
imidazopyridyl and the like. Exemplary substituents include one or more
of the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy,
protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy,
halogen, amido, amino, cyano, ketals, acetals, esters and ethers.

[0107]The terms "hydrocarbon" and "hydrocarbyl" as used herein describe
organic compounds or radicals consisting exclusively of the elements
carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and
aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and
aryl moieties substituted with other aliphatic or cyclic hydrocarbon
groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise
indicated, these moieties preferably comprise 1 to 20 carbon atoms.

[0108]The "substituted hydrocarbyl" moieties described herein are
hydrocarbyl moieties which are substituted with at least one atom other
than carbon, including moieties in which a carbon chain atom is
substituted with a hetero atom such as nitrogen, oxygen, silicon,
phosphorous, boron, sulfur, or a halogen atom. These substituents include
halogen, heterocyclo, alkoxy, alkenoxy, aryloxy, hydroxy, protected
hydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals,
acetals, esters and ethers.

[0109]Having described the invention in detail, it will be apparent that
modifications and variations are possible without departing from the
scope of the invention defined in the appended claims.

EXAMPLES

[0110]The following non-limiting examples are provided to further
illustrate the present invention.

Example 1

Preparation of Compound 711 from Compound 611 and Compound 712 from
Compound 612

##STR00014##

[0112]To a 5 L dried reactor under inert atmosphere, was added
acetonitrile (1.4 L, anhydrous). To the acetonitrile, triethylamine
(455.8 g, 4.5 moles) was introduced. The reaction flask was chilled to
5° C. 98% Formic acid (548.1, 8.75 moles) was added dropwise while
maintaining the temperature below 30° C. After the formic acid was
added, the formed salt solution was degassed for 1 hour. Compound 610
(434.5, 1.36 moles) was added all at once followed by 3.0 g
dichloro(p-cymene) ruthenium (II) dimer and 3.0 g of
(1S,2S)-(+)-N-4-toluenesulfonyl)-1,2-diphenylethylene-1,2-diamine. When
Compound 610 was used as the starting material, an additional 1.0
equivalent of 98% formic acid was added to convert the Na salt to the
phenol in situ. The reaction initially turned green, then slowly changed
to yellow. The reaction mixture was stirred for 16 hours at room
temperature. HPLC indicated the reaction was complete. The product,
Compound 711 (460 g, 97.9% yield, 97.3% assay, 99% e.e. (R)), was
isolated by filtering the solid and washing it with acetonitrile (500 mL)
followed by drying overnight (40° C., 30 in Hg). Typically, the
yields of this reaction were 95% and the enantiomeric excess was 95% R.
When (1R,2R)-(-)-N-4-toluenesulfonyl)-1,2-diphenylethylene-1,2-diamine
was substituted for
(1S,2S)-(+)-N-4-toluenesulfonyl)-1,2-diphenylethylene-1,2-di amine in
this process the S-enantiomer of Compound 711 was produced.

[0113]To produce Compound 711 in high enantiomeric purity, a general ratio
of the reactants must be maintained. For example, a ratio of about 2
equivalents of triethylamine to 5 equivalents of formic acid is desired.
Thus, generally, a ratio of about 3.2 to 3.3 equivalents of triethylamine
to 7.8 to 7.9 equivalents of 98% formic acid was used. Typically, about
0.5 wt % to 1.5 wt % of Ru catalyst and chiral ligand was used. The
reaction time directly depends on the catalyst and ligand loading; for
example, lower catalyst and ligand loading results in a longer reaction
time.

Example 2

Preparation of Compound 811 from Compound 711

##STR00015##

[0115]To a 5 L dried reaction flask was added Compound 711 (392.5 g, 1.14
moles), isopropyl alcohol (500 mL, anhydrous), and tetrahydrofuran (1.0
L, anhydrous, inhibitor free). The obtained slurry was cooled to
-60° C. Anhydrous ammonia (approximately 1.5 L) was condensed into
the slurry. The mixture was stirred for 30 minutes while maintaining the
temperature at -60° C. Then, lithium metal (30.2 g, 4.35 moles)
was added to the reaction mixture in 5 portions over an hour period.
After the last addition, the color of the reaction was blue. HPLC
analysis indicated the reaction was complete. Then, anhydrous methanol
(400 mL) was added dropwise. After the addition was complete, the
reaction mixture was slowly warmed to room temperature (approximately 8
hours with good stirring) allowing excess ammonia to evaporate. Distilled
water (750 mL) was added to the mixture. After stirring for 30 minutes,
glacial acetic acid was added slowly to a pH of 9.5 to 10. After stirring
for 1 hour, the product, Compound 811 (330.1 g, 96% yield, 98.6% e.e.
(R)), was isolated by filtration after washing the solid with distilled
water (1.0 L) and drying under vacuum (30C, 30 in Hg, 48 hours).

[0116]Generally, the solvent ratio of isopropyl alcohol (IPA) to
tetrahydrofuran (THF-anhydrous) to liquid ammonia is about 1 to 2 to 3.
Depending on the activity of the lithium metal about 1 to 30 equivalents
are used. The lithium metal was added until electron transfer (blue
color) was observed.

Example 3

Preparation of Compound 711 from Compound 611

##STR00016##

[0118]Triethylamine (1.06 g per gram of Compound 611) and acetonitrile (6
mL per gram of Compound 611) were added to a reactor equipped with a
mechanical stirrer. Formic acid (1.2 g per gram of Compound 611) was
added in four portions to the reactor resulting in an exotherm. The
reaction temperature was controlled below 80° C. during the
addition. After cooling to room temperature, a solution of 5 equivalents
formic acid to 2 equivalents triethylamine in acetonitrile was formed.
Compound 611 was added to form a suspension. It was flushed with nitrogen
for 15 min and the Ru catalyst 111 described below (0.01 g per gram of
Compound 611) was added. The suspension was again flushed with nitrogen
for 15 minutes and stirred at room temperature for 10 hours. The end
point of the reaction was determined by HPLC (Compounds 711:611 were
>99:1). The mixture was diluted with water (9 mL per gram of Compound
611) until dissolved. To the solution, 28% ammonium hydroxide (1.0 mL per
gram of Compound 611) was added to give a precipitate. The pH of the
mixture was further adjusted with ammonium hydroxide (28%) to about
9.3-9.7. The resulting suspension was filtered and the solid obtained was
washed with water (3×1.0 mL per gram of Compound 611) and dried
under vacuum (20 inches) and flowing nitrogen at 60° C. for 20
hours to give the product as an off-white solid. Yields ranged from 80%
to 95% and R:S ratio was 95:5 (90% e.e.).

Example 4

Preparation of Compound 711 from Compound 611

[0119]Table 1 shows that the results for the catalytic asymmetric
reduction of Compound 611 to Compound 7111 The reaction was carried out
in either acetonitrile (CH3CN) or methylene chloride
(CH2Cl2) at room temperature using from 0.5 mol % to 2 mol %
catalyst loading. Excess formic acid-triethylamine (5:2) was used as the
reducing reagent. The catalyst was prepared by combining equal amounts of
(1S,2S)-(+)-N-4-Page 18 of 28
toluenesulfonyl)-1,2-diphenylethylene-1,2-diamine and either
dichloro(p-cymene) ruthenium (11) dimer (catalyst 111), dichloro(benzene)
ruthenium (II) dimer (catalyst 112), or dichloro(mesitylene) ruthenium
(II) dimer (catalyst 114). The yields and enantioselectivity resulting
from the asymmetric reduction are listed in table 1.

[0121]The results in Table 2 show that Compound 613 (the salt of Compound
611) can be directly reduced to Compound 711 using the reaction
conditions of Table 1 with excess base. The reactions of Table 2 were
carried out in acetonitrile with Compound 611 (1.68 mmol), 5:2 formic
acid-triethylamine (10.8 mmol), and 1 mol % Ru catalyst 111.

[0123]Triethylamine (1.06 g per gram of Compound 611) and acetonitrile (6
mL per gram of Compound 611) were added to a reactor equipped with
mechanical stirrer. Formic acid (1.2 g per gram of Compound 611) was
added in four portions to the reactor. The exothermic reaction
temperature was controlled at below 80° C. during the addition of
formic acid. The reaction mixture was cooled to room temperature to form
a solution of formic acid-triethylamine (5:2) in acetonitrile. Compound
611 was added to the solution to form a suspension. After flushing with
nitrogen for 15 minutes, the Ru catalyst 111 (0.01 g per gram of Compound
611) was added. The suspension was again flushed with nitrogen for 15
minutes and stirred at room temperature for 10 hours. The reaction
mixture was heated to 100° C. for 2 hours to form Compound 713;
Compound 713 has a formyl group attached to the nitrogen. Compound 713
was isolated as a solid by pouring the solution into an ice cold ammonium
hydroxide solution (20 mL per gram of Compound 611).

Example 7

Preparation of Compound 811 from Compound 711

##STR00019##

[0125]To a reactor, isopropyl alcohol (IPA) (2.0 mL/g of Compound 711),
tetrahydrofuran (THF) (4.0 mL/g of Compound 711) and the Compound 711
(pre-dried to the limit of detection (LOD) or <0.2% water) were added.
The suspension was cooled to -55° C. with stirring in a dry-ice
bath. Liquid ammonia (10 mL/g of Compound 711) was condensed into the
reactor at -55° C. The reaction mixture was cooled at -55°
C. and was flushed with nitrogen for 15 minutes. Sodium t-butoxide
(NaOt-Bu) (0.35 g/g of Compound 711) was added and stirred for another 15
minutes. Lithium (cut, 0.070 g/g of Compound 711) was added in three
portions to the mixture (1/3×0.070 g/g of Compound 711 in each
portion) and the temperature of the reaction mixture was maintained at
-45 to -55° C. by using a dry-ice bath and by controlling the
addition rate. The reaction mixture was stirred for 50 minutes until all
of the lithium was added. If the blue color of the reaction mixture
lasted for more than 30 minutes the reaction was complete; otherwise,
more lithium was added until the blue color persisted for 30 minutes.
Methanol (1.0 g/g of Compound 711) was added after the reaction was
determined to be complete. The reaction mixture was warmed from
-28° C. to 20° C. to remove most of the ammonia and then
stirred for another 1 hour after the temperature reached 20° C.
Water was degassed by bubbling nitrogen through it for 20 minutes and
this degassed water (10 mL/g of Compound 711) was added under nitrogen to
the above mixture. The suspension was stirred for 30 minutes (pH=12.4) to
form a solution. A solution of aqueous acetic acid (acetic acid at 0.95
ml/g of Compound 711 and H2O at 1.90 mL/g of Compound 711) was added
to form a suspension (pH 7.8). The suspension's pH was adjusted to 8.8 to
9.2 with 28% ammonium hydroxide (˜0.25 mL/g of Compound 711). The
suspension was stirred for 1 hour and filtered. The reactor was
repeatedly rinsed with water (3.0 mL/g of Compound 711) which was then
used to wash the solid filtrate. The solid was further washed with water
(3.0 mL/g of Compound 711) and dried under flowing air for 4 h and then
dried under vacuum (20 inches) at 60° C. for 20 hours to give the
product as an off-white solid in about 90% yield.

Example 8

Preparation of Compound 811 and 815 from Compound 711

##STR00020##

[0127]In order to carry out the Birch reduction at higher temperature, the
low boiling point reagent, ammonia, was replaced with higher boiling
point reagents; for example, methylamine, ethylamine, or ethylenediamine.
It was found that both methylamine and ethylamine could be used as
electron transfer reagents to give the desired product at -10° C.
to 10° C. When Li/NH2Me/THF/t-BuOH was used for the reduction
of Compound 711, 80% yield of Compound 811 was obtained as a solid. When
Li/NH2Et/THF/t-BuOH was used for the reduction of Compound 711,
Compound 811 was formed in 50% to 70% yield. The reaction of Compound 711
in the system of Li/NH2CH2CH2NH2/THF under reflux
formed undesired Compound 815.

[0128]When introducing elements of the present invention or the preferred
embodiments(s) thereof, the articles "a", "an", "the" and "said" are
intended to mean that there are one or more of the elements. The terms
"comprising", "including" and "having" are intended to be inclusive and
mean that there may be additional elements other than the listed
elements.

[0129]In view of the above, it will be seen that the several objects of
the invention are achieved and other advantageous results attained.

[0130]As various changes could be made in the above methods and
compositions without departing from the scope of the invention, it is
intended that all matter contained in the above description shall be
interpreted as illustrative and not in a limiting sense.